ORCID Profile
0000-0002-5436-6011
Current Organisations
University of Oxford Somerville College
,
University of Oxford Medical Sciences Division
,
University of Oxford Department of Paediatrics
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Publisher: Wiley
Date: 03-07-2007
Publisher: Springer Science and Business Media LLC
Date: 12-07-2022
DOI: 10.1038/S41467-022-31636-2
Abstract: Oligonucleotides that target mRNA have great promise as therapeutic agents for life-threatening conditions but suffer from poor bioavailability, hence high cost. As currently untreatable diseases come within the reach of oligonucleotide therapies, new analogues are urgently needed to address this. With this in mind we describe reduced-charge oligonucleotides containing artificial LNA-amide linkages with improved gymnotic cell uptake, RNA affinity, stability and potency. To construct such oligonucleotides, five LNA-amide monomers (A, T, C, 5mC and G), where the 3′-OH is replaced by an ethanoic acid group, are synthesised in good yield and used in solid-phase oligonucleotide synthesis to form amide linkages with high efficiency. The artificial backbone causes minimal structural deviation to the DNA:RNA duplex. These studies indicate that splice-switching oligonucleotides containing LNA-amide linkages and phosphorothioates display improved activity relative to oligonucleotides lacking amides, highlighting the therapeutic potential of this technology.
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1038/MT.2009.306
Publisher: Frontiers Media SA
Date: 30-04-2018
Publisher: The Royal Society
Date: 26-09-2014
Abstract: Long non-coding RNAs (lncRNAs) are transcripts with low protein-coding potential that represent a large proportion of the transcriptional output of the cell. Many lncRNAs exhibit features indicative of functionality including tissue-restricted expression, localization to distinct subcellular structures, regulated expression and evolutionary conservation. Some lncRNAs have been shown to associate with chromatin-modifying activities and transcription factors, suggesting that a common mode of action may be to guide protein complexes to target genomic loci. However, the functions (if any) of the vast majority of lncRNA transcripts are currently unknown, and the subject of investigation. Here, we consider the putative role(s) of lncRNAs in neurodevelopment and brain function with an emphasis on the epigenetic regulation of gene expression. Associations of lncRNAs with neurodevelopmental/neuropsychiatric disorders, neurodegeneration and brain cancers are also discussed.
Publisher: Springer Science and Business Media LLC
Date: 16-12-2021
Publisher: Proceedings of the National Academy of Sciences
Date: 12-09-2016
Abstract: Splice-switching oligonucleotide (SSO) treatment in spinal muscular atrophy (SMA) has quickly become a clinical reality, but without an effective delivery system, the practicalities of delivering SSO therapy efficiently might preclude its widespread use. Our peptide-conjugated SSOs are being designed for clinical trials for the treatment of Duchenne muscular dystrophy. Here, we report advanced phosphorodiamidate oligomer (PMO) internalizing peptide (Pip) peptides that effectively deliver SSOs bodywide and at doses an order-of-magnitude lower than required by naked SSOs in a mouse model of SMA. Furthermore, our peptide-SSO is able to deliver to the CNS of adult mice. This study thus presents an oligonucleotide showing activity in the CNS following a systemic route with peptide delivery.
Publisher: Oxford University Press (OUP)
Date: 02-12-2014
DOI: 10.1093/NAR/GKU1256
Publisher: Mary Ann Liebert Inc
Date: 06-2017
Publisher: Elsevier BV
Date: 10-2009
Publisher: Springer Science and Business Media LLC
Date: 13-07-2011
DOI: 10.1007/S00109-011-0781-Z
Abstract: RNA interference (RNAi) represents a powerful post-transcriptional gene silencing network which fine-tunes gene expression in all eukaryotic cells. The endogenous triggers of RNAi, microRNAs (miRNAs), are proposed to regulate expression of up to a third of all protein-coding genes, and have been shown to have critical roles in developmental processes including in the central nervous system and skeletal muscle. Further, many have been reported to display differential expression in various disease states. Here we describe present understanding of the biogenesis and function of miRNAs, review current knowledge of miRNA abnormalities in both human neurological and skeletal muscle disease and discuss their potential as novel disease biomarkers. Finally, we highlight the many ways in which the miRNA pathway may be targeted for therapeutic benefit.
Publisher: Cold Spring Harbor Laboratory
Date: 30-05-2012
Abstract: Mirtrons are introns that form pre-miRNA hairpins after splicing to produce RNA interference (RNAi) effectors distinct from Drosha-dependent intronic miRNAs. Here we present a design algorithm for artificial mirtrons and demonstrate, for the first time, efficient gene knockdown of myotonic dystrophy protein kinase (DMPK) target sequences in Renilla luciferase 3′ UTR and subsequently pathogenic DMPK mRNA, causative of Type I myotonic dystrophy, using artificial mirtrons cloned as eGFP introns. Deep sequencing of artificial mirtrons suggests that functional mature transcripts corresponding to the designed sequence were produced in high abundance. They were further shown to be splicing-dependent, Drosha-independent, and partially dependent on exportin-5, resulting in the precise generation of pre-miRNAs. In a murine myoblast line containing a pathogenic copy of human DMPK with more than 500 CUG repeats, the DMPK artificial mirtron corrected DM1-associated splicing abnormalities of the Serca-1 mRNA, demonstrating the therapeutic potential of mirtron-mediated RNAi. Thus, further development and exploitation of the unique properties of mirtrons will benefit future research and therapeutic RNAi applications as an alternative to conventional RNAi strategies.
Publisher: Wiley
Date: 25-06-2012
DOI: 10.1002/WRNA.1122
Abstract: Post-transcriptional gene silencing (PTGS) via RNA interference (RNAi) is a vital gene regulatory mechanism for fine-tuning gene expression. RNAi effectors termed microRNAs (miRNAs) are implicated in various aspects of animal development and normal physiological function, while dysregulation has been linked to several pathologies. Several atypical miRNA biogenesis pathways have been identified, yet in most cases the reasons for their emergence remain unclear. One of these atypical pathways is the mirtron pathway, where short introns are excised by splicing to generate intermediates of the RNAi pathway, with no cleavage by the microprocessor. Closely related pathways involving tailed-mirtron and simtron biogenesis have also been described. There is extensive evidence that mirtrons function as miRNAs, and while some are evolutionarily conserved across similar species, others appear to have emerged relatively recently. In addition, through exploitation of the potent and sequence-specific silencing capabilities of RNAi, synthetic mirtrons may have potential for overcoming certain therapeutic challenges.
Publisher: Wiley
Date: 27-02-2008
DOI: 10.1111/J.1365-2656.2008.01370.X
Abstract: 1. Seasonal variation in environmental conditions is ubiquitous and can affect the spread of infectious diseases. Understanding seasonal patterns of disease incidence can help to identify mechanisms, such as the demography of hosts and vectors, which influence parasite transmission dynamics. 2. We examined seasonal variation in Plasmodium infection in a blue tit Cyanistes caeruleus population over 3 years using sensitive molecular diagnostic techniques, in light of Beaudoin et al.'s (1971 Journal of Wildlife Diseases, 7, 5-13) model of seasonal variation in avian malaria prevalence in temperate areas. This model predicts a within-year bimodal pattern of spring and autumn peaks with a winter absence of infection. 3. Avian malaria infections were mostly Plasmodium (24.4%) with occasional Haemoproteus infections (0.8%). Statistical nonlinear smoothing techniques applied to longitudinal presence/absence data revealed marked temporal variation in Plasmodium prevalence, which apparently showed a within-year bimodal pattern similar to Beaudoin et al.'s model. However, of the two Plasmodium morphospecies accounting for most infections, only the seasonal pattern of Plasmodium circumflexum supported Beaudoin et al.'s model. On closer examination there was also considerable age structure in infection: Beaudoin et al.'s seasonal pattern was observed only in first year and not older birds. Plasmodium relictum prevalence was less seasonally variable. 4. For these two Plasmodium morphospecies, we reject Beaudoin et al.'s model as it does not survive closer scrutiny of the complexities of seasonal variation among Plasmodium morphospecies and host age classes. Studies of host-parasite interactions should consider seasonal variation whenever possible. We discuss the ecological and evolutionary implications of seasonal variation in disease prevalence.
Publisher: Research Square Platform LLC
Date: 04-05-2022
DOI: 10.21203/RS.3.RS-1542733/V1
Abstract: Oligonucleotides that target mRNA have great promise as therapeutic agents for life-threatening conditions but suffer from poor bioavailability, hence high cost. As currently untreatable diseases come within the reach of oligonucleotide therapies, new analogues are urgently needed to address this. With this in mind we have developed reduced-charge oligonucleotides containing artificial LNA-amide linkages with improved gymnotic cell uptake, RNA affinity, stability and potency. To construct such oligonucleotides, five LNA-amide monomers (A, T, C, 5mC and G), where the 3´-OH is replaced by an ethanoic acid group, were synthesised in good yield and used in solid-phase oligonucleotide synthesis to form amide linkages with high efficiency. The artificial backbone causes minimal structural deviation to the DNA:RNA duplex. These studies indicate that splice-switching oligonucleotides containing LNA-amide linkages and phosphorothioates display improved activity relative to oligonucleotides lacking amides, highlighting the therapeutic potential of this technology.
Publisher: Public Library of Science (PLoS)
Date: 21-10-2011
Publisher: Springer Science and Business Media LLC
Date: 02-03-2016
DOI: 10.1038/SREP22519
Abstract: Cells release nano-sized membrane vesicles that are involved in intercellular communication by transferring biological information between cells. It is generally accepted that cells release at least three types of extracellular vesicles (EVs): apoptotic bodies, microvesicles and exosomes. While a wide range of putative biological functions have been attributed to exosomes, they are assumed to represent a homogenous population of EVs. We hypothesized the existence of subpopulations of exosomes with defined molecular compositions and biological properties. Density gradient centrifugation of isolated exosomes revealed the presence of two distinct subpopulations, differing in biophysical properties and their proteomic and RNA repertoires. Interestingly, the subpopulations mediated differential effects on the gene expression programmes in recipient cells. In conclusion, we demonstrate that cells release distinct exosome subpopulations with unique compositions that elicit differential effects on recipient cells. Further dissection of exosome heterogeneity will advance our understanding of exosomal biology in health and disease and accelerate the development of exosome-based diagnostics and therapeutics.
Publisher: Elsevier BV
Date: 2012
DOI: 10.1038/MTNA.2012.15
Publisher: Elsevier BV
Date: 08-2011
Publisher: Springer Science and Business Media LLC
Date: 18-11-2021
DOI: 10.1038/S41467-021-27056-3
Abstract: Extracellular vesicles (EVs) are biological nanoparticles with important roles in intercellular communication, and potential as drug delivery vehicles. Here we demonstrate a role for the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in EV assembly and secretion. We observe high levels of GAPDH binding to the outer surface of EVs via a phosphatidylserine binding motif (G58), which promotes extensive EV clustering. Further studies in a Drosophila EV biogenesis model reveal that GAPDH is required for the normal generation of intraluminal vesicles in endosomal compartments, and promotes vesicle clustering. Fusion of the GAPDH-derived G58 peptide to dsRNA-binding motifs enables highly efficient loading of small interfering RNA (siRNA) onto the EV surface. Such vesicles efficiently deliver siRNA to multiple anatomical regions of the brain in a Huntington’s disease mouse model after systemic injection, resulting in silencing of the huntingtin gene in different regions of the brain.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-08-2021
Abstract: AR isoform 2–encoded variant acts as a transcriptional modulator of AR genomic activity and is a target for therapy for SBMA.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Matthew Wood.